Correlation of molecular total surface area with organotin toxicity for biological and physicochemical applications

There exists a high correlation between molecular total surface area (TSA) values and diorganotin toxicity towards several distinct types of organisms. This correlation was found for N₂a neuroblastoma cells, 3T3 fibroblasts, Daphnia magna Rhithropanopeus harrisii and Ankistrodesmus falcatus. In the case of Rhithropanopeus harrisii, a high correlation was also found between TSA and toxicity for triorganotins as well. This study suggests that the relationship between TSA and toxicity is a function of the hydrophobicity of the organotin compounds rather than electronic or steric effects.     

The structure of organometals determines cytotoxicity and alteration of calcium homeostasis in HL-60 cells

There is increasing concern about the degradation and metabolisation as well as the biochemical mechanisms of action of organometallic compounds. They are known to be immunotoxic and/or neurotoxic. Because of their different toxic capacities, the development of a reliable correlation between molecular parameters and biochemical effects, which could be helpful in risk assessment, was an aim of this study. The tested organolead and -tin compounds decrease the viability of human cells in culture in a time- and concentration-dependent manner. Parabolic QSAR(1)(1) The abbreviations used are: TMT, trimethyltin chloride; TET, triethyltin bromide; TPT, tripropyltin chloride; TBT, tri- n-butyltin chloride; DBT, di- n-butyltin dichloride; TEL, triethyllead chloride; DEL, diethyllead dichloride; TML, trimethyllead chloride; TPhL, triphenyllead chloride; QSAR, quantitative structure-activity relationships; TSA, total surface area; MW(ion), ionic molecular weight; fMLP, N-formyl-L-methionyl-L-leucyl-L-phenylalanine; fluo-3, fluo-3 free acid; fluo-3 AM, fluo-3 acetoxymethyl ester; Me(2)SO, dimethyl sulfoxide; PLA(2), phospholipase A(2) (EC 3.1.1.4); FCS, fetal calf serum; HEPES, 4-(2-hydroxy-ethyl)-1-piperazineethanesulfonic acid; EGTA, [ethylene-bis(oxyethylenenitrilo)]tetraacetic acid; [Ca(2+)](i), cytosolic free Ca(2+) concentration models yield an adequate correlation between toxicity expressed as LC(50) and structural parameters like ionic molecular weight (MW(ion)) or total surface area (TSA). Two main chemical attributes of the organometals are probably responsible for such a parabolic relationship: the hydrophobic side chain and the polar metal atom. Furthermore, all tested organometal compounds evoke a persistent increase of the cytosolic free calcium concentration [Ca(2+)](i). This effect is mainly due to an influx from the extracellular space. Further results suggest that Ca(2+) enters the cell via opened calcium channels. Based on the essential role of Ca(2+) within cellular signalling, the perturbation of calcium homeostasis appears to be an important event in final cell killing by organometals and it is most likely that other biochemical mechanisms, e.g. activation of phospholipase A(2), are possibly mediated by an increase of [Ca(2+)](i).     

The structure of organometals determines cytotoxicity and alteration of calcium homeostasis in HL-60 cells

There is increasing concern about the degradation and metabolisation as well as the biochemical mechanisms of action of organometallic compounds. They are known to be immunotoxic and/or neurotoxic. Because of their different toxic capacities, the development of a reliable correlation between molecular parameters and biochemical effects, which could be helpful in risk assessment, was an aim of this study. The tested organolead and -tin compounds decrease the viability of human cells in culture in a time- and concentration-dependent manner. Parabolic QSAR¹¹ The abbreviations used are: TMT, trimethyltin chloride; TET, triethyltin bromide; TPT, tripropyltin chloride; TBT, tri-n-butyltin chloride; DBT, di-n-butyltin dichloride; TEL, triethyllead chloride; DEL, diethyllead dichloride; TML, trimethyllead chloride; TPhL, triphenyllead chloride; QSAR, quantitative structure-activity relationships; TSA, total surface area; MW_ion, ionic molecular weight; fMLP, N-formyl-L-methionyl-L-leucyl-L-phenylalanine; fluo-3, fluo-3 free acid; fluo-3 AM, fluo-3 acetoxymethyl ester; Me₂SO, dimethyl sulfoxide; PLA₂, phospholipase A₂ (EC 3.1.1.4); FCS, fetal calf serum; HEPES, 4-(2-hydroxy-ethyl)-1-piperazineethanesulfonic acid; EGTA, [ethylene-bis(oxyethylenenitrilo)]tetraacetic acid; [Ca²⁺]_i, cytosolic free Ca²⁺ concentration models yield an adequate correlation between toxicity expressed as LC₅₀ and structural parameters like ionic molecular weight (MW_ion) or total surface area (TSA). Two main chemical attributes of the organometals are probably responsible for such a parabolic relationship: the hydrophobic side chain and the polar metal atom. Furthermore, all tested organometal compounds evoke a persistent increase of the cytosolic free calcium concentration [Ca²⁺]_i. This effect is mainly due to an influx from the extracellular space. Further results suggest that Ca²⁺ enters the cell via opened calcium channels. Based on the essential role of Ca²⁺ within cellular signalling, the perturbation of calcium homeostasis appears to be an important event in final cell killing by organometals and it is most likely that other biochemical mechanisms, e.g. activation of phospholipase A₂, are possibly mediated by an increase of [Ca²⁺]_i.     

Joint QSAR Analysis Using the Free-Wilson Approach and Quantum Chemical Parameters

Abstract

A new quantitative structure-activity relationship (QSAR) technique combining the Free-Wilson method and constructed quantum chemical parameters was used to simulate the aqueous solubility (S _w), 1-octanol/water partition coefficient (K _ow) of 14 new synthesized benzanilide derivatives and their 96 h acute toxicity (EC₅₀) to Daphnia magna. The mode of action of the 14 selected compounds to Daphnia magna was shown to be a complex process involving a physical partition stage and a biochemical reaction stage. The results also indicated that the joint (QSAR) analysis was much effective than the original Free-Wilson method and Hansch method not only in predicting properties/toxicity, but also in investigating the mode of action of chemicals.     

离子液体的定量结构-性质/活性研究

本文系统介绍了离子液体定量结构-性质/活性相关(QSPR/QSAR)的研究方法和步骤,综述了QSPR/QSAR在离子液体的熔点、有机物在离子液体中的无限稀释活度系数、离子液体的表面张力、离子液体的电导率、有机物在离子液体中的溶解度、离子液体的黏度以及离子液体的生物毒性和降解性等方面的最新研究进展,总结了该方法的优缺点,并对未来的研究趋势进行了展望。     

QSAR and docking studies on chalcone derivatives for antitubercular activity against M. tuberculosis H37Rv

In our prior studies, we reported some known antitubercular drugs (rifampicin and streptomycin) and newly synthesized chalcone derivatives (16–26) tested in vitro against Mycobacterium tuberculosis H₃₇Rv strain. Most of the tested compounds were efficient antimycobacterial agents showing minimum inhibitory concentration values ranging from 3.5 to 30 µg mL⁻¹. In the present work, a quantitative structure–activity relationship (QSAR) study has been performed on these active chalcone derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. A QSAR model that is able to correlate well the antitubercular activity with the chemical structures of active chalcone derivatives 16, 24, 25a, 25c, and 26 has been developed, which is potentially helpful in the design of novel and more potent antitubercular agents. The r² and rCV² of a newly derived QSAR model were 0.89 and 0.84, respectively. The QSAR study indicates that chemical properties, viz. heat of formation (kcal mol⁻¹), lowest unoccupied molecular orbital energy (eV), and amine, hydroxyl, and methyl groups counts, correlate well with the activity. In silico screening results for oral bioavailability and absorption, distribution, metabolism, excretion, and toxicity compliance showed that compounds 25a, 25c, and 24 were found active similar to rifampicin and streptomycin. The docking study for the exploration of mechanism of action showed high binding affinity of active derivatives. Copyright © 2014 John Wiley & Sons, Ltd.     

药物水溶解度的QSAR研究和VolSurf参数

药物的水溶解度与其吸收密切相关。本文利用一种新的计算方法,VolSurf,预测药物的水溶解度并测定有利于药物水溶解度的主要分子特征。被测化合物包括26个结构不同的药物,通过偏最小二乘分析法,对药物水溶解度实验值与分子特征进行相关,得到较好的模型(r2=0.90,q2=0.77)。将化合物分为训练集和预测集进行相关分析,结果表明以18个化合物所建立的训练集模型对其余8个化合物有较好的预测能力,预测的标准偏差(SDEP)为0.59。参数分析表明分子与水相互作用的3个局部能量最小值越小,且它们之间的距离越大,对其水溶解度越有利;亲水性占主导因素的分子有高的水溶解度;分子的疏水性越强,在水中的溶解性越弱;大分子的溶解度较小分子溶解度低。     

Toxicity of butyltin,phenyltin and inorganic tin compounds to sulfate‐reducing bacteria isolated from anoxic marine sediments

The toxicity of butyltin, phenyltin and inorganic tin compounds to three pure strains of sulfate‐reducing bacteria (SRB), isolated from a tributyltin (TBT)‐polluted sediment, was determined. The isolated strains were identified as belonging to the genus Desulfovibrio. A new toxicological index (GR₂₅) was developed to assay the toxicity of organotin compounds. Deleterious effects on suspended anaerobic cell cultures were observed for concentrations ranging between 500 and 600 µM for tin tetrachloride, 55 and 260 µM for triorganotins, 30 and 90 µM for diorganotins, and 1 and 6 µM for mono‐organotins. Whereas the number of substituents influenced the toxicity of organotins, the type of substituent (butyl or phenyl) proved to have little or no impact. Trisubstituted compounds (tributyl‐ and triphenyl‐tin) were less toxic to these strains of SRB than the monosubstituted forms (monobutyl‐ and monophenyl‐tin). This is the opposite trend to that currently reported for aerobic organisms. Under the given anoxic conditions, the toxicity of organotin compounds obtained yielded a significant negative correlation with the total surface area (TSA) of the tested molecules. Comparison of the TBT toxicity data observed for different microbial groups suggests that the tolerance of bacteria to organotin compounds might be related to organotin–cell wall interactions as well as to aerobic or anaerobic metabolise pathways. Copyright © 2000 John Wiley & Sons, Ltd.     

DFT‐based QSAR study and molecular design of AHMA derivatives as potent anticancer agents

A quantitative structure–activity relationship (QSAR) of 3‐(9‐acridinylamino)‐5‐hydroxymethylaniline (AHMA) derivatives and their alkylcarbamates as potent anticancer agents has been studied using density functional theory (DFT), molecular mechanics (MM+), and statistical methods. In the best established QSAR equation, the energy (E_NL) of the next lowest unoccupied molecular orbital (NLUMO) and the net charges (Q_FR) of the first atom of the substituent R, as well as the steric parameter (MR₂) of subsituent R₂ are the main independent factors contributing to the anticancer activity of the compounds. A new scheme determining outliers by “leave‐one‐out” (LOO) cross‐validation coefficient (q) was suggested and successfully used. The fitting correlation coefficient (R²) and the “LOO” cross‐validation coefficient (q²) values for the training set of 25 compounds are 0.881 and 0.829, respectively. The predicted activities of 5 compounds in the test set using this QSAR model are in good agreement with their experimental values, indicating that this model has excellent predictive ability. Based on the established QSAR equation, 10 new compounds with rather high anticancer activity much greater than that of 34 compounds have been designed and await experimental verification. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

QSAR models for P450 (2D6) substrate activity

Human Cytochrome P450 (CYP) is a large group of enzymes that possess an essential function in metabolising different exogenous and endogenous compounds. Humans have more than 50 different genes encoding CYP enzymes, among these a gene encoding for the CYP isoenzyme 2D6, a CYP able to metabolise drugs and other chemicals. A training set of 747 chemicals primarily based on in vivo human data for the CYP isoenzyme 2D6 was collected from the literature. QSAR models focusing on substrate/non-substrate activity were constructed by the use of MultiCASE, Leadscope and MDL quantitative structure–activity relationship (QSAR) modelling systems. They cross validated (leave-groups-out) with concordances of 71%, 81% and 82%, respectively. Discrete organic European Inventory of Existing Commercial Chemical Substances (EINECS) chemicals were screened to predict an approximate percentage of CYP 2D6 substrates. These chemicals are potentially present in the environment. The biological importance of the CYP 2D6 and the use of the software mentioned above were discussed.     

QSAR analysis of 1,3-diaryl-2-propen-1-ones and their indole analogs for designing potent antibacterial agents

A series of 1,3-diaryl-2-propen-1-ones and their indole analogs were synthesized and evaluated for antibacterial activity. Structures of newly synthesized compounds were confirmed by physicochemical, spectral and elemental analysis. All the compounds were screened for their antibacterial activities against four different bacterial strains. The QSAR studies were performed using Vlife MDS 3.5 software. QSAR equation revealed that selected electronic, steric and lipophilic parameters have good correlation with antibacterial activity. Best equations were selected on basis of the correlation coefficient (r ²) and the predictable ability of the equations. The present findings suggest that the 1,3-diaryl-2-propen-1-ones framework is an attractive template for structure optimization to achieve higher potency, lower toxicity, and a wider spectrum of antibacterial activity.     

异喹啉类化合物抑制肥大细胞脱颗粒活性的3D-QSAR研究

对一组抑制肥大细胞脱颗粒的异喹啉类化合物的活性及毒性进行了3D-QSAR研究,采用距离比较法(DISCO)得到了它们的药效团模型,通过选择不同的叠合方式,建立了相关性很好的比较分子力场分析(CoMFA)模型,其交叉验证参数R^2~cv分别为0.654和0.662,非交叉验证的相关系数分别为0.990与0.983,通过查阅统计量F表,表明活性及毒性模型的置信度都大于99%,显示模型具有较强的预测能力,并在此基础上进行了新活性先导化合物的设计,得到了预测活性高以及预测毒性低的新结构,合成实验正在进行之中。